Date of Award

Summer 8-12-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Dr. Julie A. Blendy

Abstract

Mood disorders are associated with deficits in hippocampal size and function. Neurogenesis in the dentate gyrus of the hippocampus has been implicated in the behavioral efficacy of some antidepressants. However, the precise function of newborn hippocampal neurons in the etiology and treatment of mood disorders remains unclear. Anxiety, which is highly comorbid with mood disorders, also appears to be influenced by neurogenesis. The intricacies of this influence are poorly understood. Here, the role of neurogenesis in the pathophysiology and treatment of mood and anxiety disorders is investigated in a transgenic mouse exhibiting partial suppression of hippocampal neurogenesis. This reduction is induced by hippocampal microinjection of a Cre-expressing adeno-associated virus to delete ATR, a cell cycle checkpoint kinase, from the hippocampus of adult mice. Subsequent to hippocampal ATR deletion, behavior is examined in mouse models of anxiety, depressive-like behavior, antidepressant efficacy, and susceptibility to stress. In addition, the necessity of heightened neurogenesis in exercise-induced anxiety is examined. ATR deletion resulted in an anhedonic phenotype in a sucrose drinking task but did not increase the likelihood of developing behavioral despair in the learned helplessness paradigm. Furthermore, mice lacking hippocampal ATR exhibited reduced anxiety in a number of behavioral tests. In the novelty-induced hypophagia task, the ability of chronic antidepressants to alleviate hyponeophagia was absent in ATR-deleted mice, and this effect was linked to an attenuation of the ability of chronic antidepressants to stimulate dendritic spine density. Finally, ATR deletion attenuated the neurogenic effect of voluntary wheel running, and concurrently blocked some of the anxiogenic effects of wheel running. In conclusion, neurogenesis appears to be an essential regulator of behaviors indicative of mood and anxiety disorders. These observations contribute to the body of work investigating the etiology and treatment of mood disorders for the purpose of guiding pharmaceutical drug discovery towards the eventual identification of antidepressant compounds with greater efficacy and fewer side effects.

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